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Genetics of Breast and Gynecologic Cancers (PDQ®)

Introduction

General Information

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes and conditions described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

Among women, breast cancer is the most commonly diagnosed cancer after
nonmelanoma skin cancer, and it is the second leading cause of cancer deaths after
lung cancer. In 2015, an estimated 234,190 new cases will be diagnosed, and
40,730 deaths from breast cancer will occur.[1] The incidence of breast cancer, particularly for estrogen receptor–positive cancers occurring after age 50 years, is declining and has declined at a faster rate since 2003; this may be temporally related to a decrease in hormone replacement therapy (HRT) after early reports from the Women’s Health Initiative (WHI).[2] An estimated 21,290 new cases of ovarian cancer are expected in 2015, with an estimated 14,180 deaths. Ovarian cancer is the fifth most deadly cancer in women.[1] An estimated 54,870 new cases of endometrial cancer are expected in 2015, with an estimated 10,170 deaths.[1] (Refer to the PDQ summaries on Breast Cancer Treatment; Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment; and Endometrial Cancer Treatment for more information about breast, ovarian, and endometrial cancer rates, diagnosis, and management.)

A possible genetic contribution to both breast and ovarian cancer risk is indicated by the
increased incidence of these cancers among women with a family history (refer to the Risk Factors for Breast Cancer, Risk Factors for Ovarian Cancer, and Risk Factors for Endometrial Cancer sections below for more information), and by the observation of some families in which multiple family
members are affected with breast and/or ovarian cancer, in a pattern compatible with an inheritance of autosomal dominant cancer susceptibility. Formal studies of families (linkage analysis) have subsequently proven the
existence of autosomal dominant predispositions to breast and ovarian cancer and have led to the
identification of several highly penetrantgenes as the cause
of inherited cancer risk in many families. (Refer to the PDQ
summary Cancer Genetics Overview for more information about linkage
analysis.) Mutations in these genes are rare in the general population and are estimated to account for no more
than 5% to 10% of breast and ovarian cancer cases overall. It is likely that other
genetic factors contribute to the etiology of some of these cancers.

Risk Factors for Breast Cancer

Refer to the PDQ summary on Breast Cancer Prevention
for information about risk factors for breast cancer in the general population.

Family history including inherited cancer genes

In cross-sectional studies of adult populations, 5% to 10% of women have a
mother or sister with breast cancer, and about twice as many have either a first-degree relative (FDR) or a second-degree relative with breast cancer.[3-6] The risk
conferred by a family history of breast cancer has been assessed in case-control and cohort studies, using volunteer and population-based samples,
with generally consistent results.[7] In a pooled analysis of 38 studies, the
relative risk (RR) of breast cancer conferred by an FDR with breast
cancer was 2.1 (95% confidence interval [CI], 2.0–2.2).[7] Risk increases with the number of affected relatives, age at diagnosis, and the number of affected male relatives.[4,5,7,8] (Refer to the Penetrance of mutations section of this summary for a discussion of familial risk in women from families with BRCA1/BRCA2 mutations who themselves test negative for the family mutation.)

Age

Cumulative risk of breast cancer increases with age, with most breast cancers
occurring after age 50 years.[9] In women with a genetic susceptibility, breast
cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases.

Reproductive and menstrual history

In general, breast cancer risk increases with early menarche and late menopause and is
reduced by early first full-term pregnancy. In BRCA1 and BRCA2 mutation carriers, results have been conflicting and may be gene dependent. No consistent significant associations have been observed.[10-13] Evidence suggests that reproductive history may be differentially associated with breast cancer subtype (i.e., triple-negative vs. estrogen receptor [ER]-positive breast cancers). In contrast to ER-positive breast cancers, parity has been positively associated with triple-negative disease, with no association with ages at menarche and menopause.[14]

Oral contraceptives

Oral contraceptives (OCs) may produce a slight increase in breast cancer risk among
long-term users, but this appears to be a short-term effect. In a meta-analysis
of data from 54 studies, the risk of breast cancer associated with OC use did not vary in relationship to a family history of breast cancer.[15]

OCs are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers. Although the data are not entirely consistent, a meta-analysis concluded that there was no significant increased risk of breast cancer with OC use in BRCA1/BRCA2 mutation carriers.[16] However, use of OCs formulated before 1975 was associated with an increased risk of breast cancer (summary relative risk [SRR], 1.47; 95% CI, 1.06–2.04).[16] (Refer to the Reproductive factors section in the Clinical Management of BRCA Mutation Carriers section of this summary for more information.)

Hormone replacement therapy

Data exist from both observational and randomized clinical trials regarding the association between postmenopausal HRT and breast cancer. A meta-analysis of data from 51
observational studies indicated a RR of breast cancer of 1.35 (95% CI, 1.21–1.49)
for women who had used HRT for 5 or more years after menopause.[17] The WHI (NCT00000611), a randomized controlled trial of about 160,000 postmenopausal women, investigated the risks and benefits of HRT. The estrogen-plus-progestin arm of the study, in which more than 16,000 women were randomly assigned to receive combined HRT or placebo, was halted early because health risks exceeded benefits.[18,19] Adverse outcomes prompting closure included significant increase in both total (245 vs. 185 cases) and invasive (199 vs. 150 cases) breast cancers (RR, 1.24; 95% CI, 1.02–1.5, P <. 001) and increased risks of coronary heart disease, stroke, and pulmonary embolism. Similar findings were seen in the estrogen-progestin arm of the prospective observational Million Women’s Study in the United Kingdom.[20] The risk of breast cancer was not elevated, however, in women randomly assigned to estrogen-only versus placebo in the WHI study (RR, 0.77; 95% CI, 0.59–1.01). Eligibility for the estrogen-only arm of this study required hysterectomy, and 40% of these patients also had undergone oophorectomy, which potentially could have impacted breast cancer risk.[21]

The association between HRT and breast cancer risk among women with a family history of breast cancer has not been consistent; some studies suggest risk is particularly elevated among women with a family history, while others have not found evidence for an interaction between these factors.[22-26,17]
The increased risk of breast cancer associated with HRT use in the large meta-analysis did not differ significantly between subjects with and without a family history.[26] The WHI study has not reported analyses stratified on breast cancer family history, and subjects have not been systematically tested for BRCA1/BRCA2 mutations.[19] Short-term use of hormones for treatment of menopausal symptoms appears to
confer little or no breast cancer risk.[17,27] The effect of HRT on breast cancer risk among carriers of BRCA1 or BRCA2 mutations has been studied only in the context of bilateral risk-reducing oophorectomy, in which short-term replacement does not appear to reduce the protective effect of oophorectomy on breast cancer risk.[28] (Refer to the Hormone replacement therapy in BRCA1/BRCA2 mutation carriers section of this summary for more information.)

Radiation exposure

Observations in survivors of the atomic bombings of Hiroshima and Nagasaki and in women who have received
therapeutic radiation treatments to the chest and upper body document increased
breast cancer risk as a result of radiation exposure. The significance of this
risk factor in women with a genetic susceptibility to breast cancer is unclear.

Preliminary data suggest that increased sensitivity to
radiation could be a cause of cancer susceptibility in carriers of BRCA1 or
BRCA2 mutations,[29-32] and in association with germline ATM and TP53 mutations.[33,34]

The possibility that genetic susceptibility to breast cancer occurs via a
mechanism of radiation sensitivity raises questions about radiation exposure.
It is possible that diagnostic radiation exposure, including mammography, poses
more risk in genetically susceptible women than in women of average risk.
Therapeutic radiation could also pose carcinogenic risk. A cohort study of
BRCA1 and BRCA2 mutation carriers treated with breast-conserving therapy,
however, showed no evidence of increased radiation sensitivity or sequelae in
the breast, lung, or bone marrow of mutation carriers.[35] Conversely,
radiation sensitivity could make tumors in women with genetic susceptibility to
breast cancer more responsive to radiation treatment. Studies examining the impact of radiation exposure, including, but not limited to, mammography, in BRCA1 and BRCA2 mutation carriers have had conflicting results.[36-40] A large European study showed a dose-response relationship of increased risk with total radiation exposure, but this was primarily driven by nonmammographic radiation exposure before age 20 years.[40] (Refer to the Mammography section in the Clinical Management of BRCA Mutation Carriers section of this summary for more information about radiation.)

Alcohol intake

The risk of breast cancer increases by approximately 10% for each 10 g of daily alcohol intake (approximately one drink or less) in the general population.[41,42] Prior studies of BRCA1/BRCA2 mutation carriers have found no increased risk associated with alcohol consumption.[43,44]

Physical activity and anthropometry

Weight gain and being overweight are commonly recognized risk factors for
breast cancer. In general, overweight women are most commonly observed to be at increased
risk of postmenopausal breast cancer and at reduced risk of premenopausal
breast cancer. Sedentary lifestyle may also be a risk factor.[45] These factors
have not been systematically evaluated in women with a positive family history of breast
cancer or in carriers of cancer-predisposing mutations, but one study suggested a reduced risk of cancer associated with exercise among BRCA1 and BRCA2 mutation carriers.[46]

Benign breast disease and mammographic density

Benign breast disease (BBD) is a risk factor for breast cancer, independent of
the effects of other major risk factors for breast cancer (age, age at
menarche, age at first live birth, and family history of breast cancer).[47] There may also be an association between BBD and family history of breast cancer.[48]

An increased risk of breast cancer has also been demonstrated for women who
have increased density of breast tissue as assessed by mammogram,[47,49,50] and breast density is likely to have a genetic component in its etiology.[51-53]

Other factors

Other risk factors, including those that are only weakly associated with breast
cancer and those that have been inconsistently associated with the disease in
epidemiologic studies (e.g., cigarette smoking), may be important in women who are in specific genotypically defined subgroups. For example, some studies have
suggested that certain N-acetyl transferase alleles may influence female
smokers’ risk of developing breast cancer.[54] One study [55] found a reduced risk of breast cancer among BRCA1/BRCA2 mutation carriers who smoked, but an expanded follow-up study failed to find an association.[56]

Risk Factors for Ovarian Cancer

Refer to the PDQ summary on Ovarian Cancer Prevention for information about risk factors for ovarian cancer in the general population.

Family history including inherited cancer genes

Although reproductive, demographic, and lifestyle
factors affect risk of ovarian cancer, the single greatest ovarian cancer risk
factor is a family history of the disease. A large meta-analysis of 15 published studies estimated an odds ratio of 3.1 for the risk of ovarian cancer associated with at least one FDR with ovarian cancer.[57]

Age

Ovarian cancer incidence rises in a linear fashion from age 30 years to age 50 years and continues to increase, though at a slower rate, thereafter. Before age 30 years, the risk of developing epithelial ovarian cancer is remote, even in hereditary cancer families.[58]

Reproductive
history

Nulliparity is consistently associated with an increased risk of ovarian cancer, including among BRCA1/BRCA2 mutation carriers.[59] Risk may also be increased among women who have used fertility drugs, especially those who remain nulligravid.[60,61] Evidence is growing that the use of menopausal HRT is associated with an increased risk of ovarian cancer, particularly in long-time users and users of sequential estrogen-progesterone schedules.[62-65]

Surgical history

Bilateral tubal ligation and hysterectomy are associated with reduced ovarian cancer risk,[60,66,67] including in BRCA1/BRCA2 mutation carriers.[68] Ovarian cancer risk is reduced more than 90% in women with documented BRCA1 or BRCA2 mutations who chose risk-reducing salpingo-oophorectomy. In this same population, prophylactic removal of the ovaries also resulted in a nearly 50% reduction in the risk of subsequent breast cancer.[69,70] (Refer to the Risk-reducing salpingo-oophorectomy section of this summary for more information about these studies.)

Oral contraceptives

Use of OCs for 4 or more years is associated with an approximately 50% reduction in ovarian cancer risk in the general population.[60,71] A majority of, but not all, studies also support OCs being protective among BRCA1/ BRCA2 mutation carriers.[59,72-75] A meta-analysis of 18 studies including 13,627 BRCA mutation carriers reported a significantly reduced risk of ovarian cancer (SRR, 0.50; 95% CI, 0.33–0.75) associated with OC use.[16] (Refer to the Oral contraceptives section in the Chemoprevention section of this summary for more information.)

Risk Factors for Endometrial Cancer

Family history including inherited cancer genes

Although the hyperestrogenic state is the most common predisposing factor for endometrial cancer, family history also plays a significant role in a woman’s risk for disease. Approximately 3% to 5% of uterine cancer cases are attributable to a hereditary cause,[76] with the main hereditary endometrial cancer syndrome being Lynch syndrome (LS), an autosomal dominant genetic condition with a population prevalence of 1 in 300 to 1 in 1,000 individuals.[77,78] (Refer to the LS section in the PDQ summary on Genetics of Colorectal Cancer for more information.)

Age

Age is an important risk factor for endometrial cancer. Most women with endometrial cancer are diagnosed after menopause. Only 15% of women are diagnosed with endometrial cancer before age 50 years, and fewer than 5% are diagnosed before age 40 years.[79]
Women with LS tend to develop endometrial cancer at an earlier age, with the median age at diagnosis of 48 years.[80]

Reproductive history

Reproductive factors such as multiparity, late menarche, and early menopause decrease the risk of endometrial cancer because of the lower cumulative exposure to estrogen and the higher relative exposure to progesterone.[81,82]

Hormones

Hormonal factors that increase the risk of type I endometrial cancer are better understood. All endometrial cancers share a predominance of estrogen relative to progesterone. Prolonged exposure to estrogen or unopposed estrogen increases the risk of endometrial cancer. Endogenous exposure to estrogen can result from obesity, polycystic ovary syndrome (PCOS), and nulliparity, while exogenous estrogen can result from taking unopposed estrogen or tamoxifen. Unopposed estrogen increases the risk of developing endometrial cancer by twofold to twentyfold, proportional to the duration of use.[83,84] Tamoxifen, a selective estrogen receptor modulator, acts as an estrogen agonist on the endometrium while acting as an estrogen antagonist in breast tissue, and increases the risk of endometrial cancer.[85] In contrast, oral contraceptives, the levonorgestrel-releasing intrauterine system, and combination estrogen-progesterone hormone replacement therapy all reduce the risk of endometrial cancer through the antiproliferative effect of progesterone acting on the endometrium.[86-89]

Autosomal dominant inheritance of breast and gynecologic cancers is characterized by transmission of
cancer predisposition from generation to generation, through either the mother’s or the father’s
side of the family, with the following characteristics:

Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.

Both males and females can inherit and transmit an autosomal dominant
cancer predisposition. A male who
inherits a cancer predisposition can still
pass the altered gene on to his sons and daughters.

Breast and ovarian cancer are components of several autosomal dominant cancer syndromes. The syndromes most strongly associated with both cancers are the BRCA1 or BRCA2 mutation syndromes. Breast cancer is also a common feature of Li-Fraumeni syndrome due to TP53 mutations and of Cowden syndrome due to PTEN mutations.[90] Other genetic syndromes that may include breast cancer as an associated feature include heterozygous carriers of the ataxia telangiectasia gene and Peutz-Jeghers syndrome. Ovarian cancer has also been associated with LS, basal cell nevus (Gorlin) syndrome (OMIM), and multiple endocrine neoplasia type 1 (OMIM).[90] LS is mainly associated with colorectal cancer and endometrial cancer, although several studies have demonstrated that patients with LS are also at risk of developing transitional cell carcinoma of the ureters and renal pelvis; cancers of the stomach, small intestine, liver and biliary tract, brain, breast, prostate, and adrenal cortex; and sebaceous skin tumors (Muir-Torre syndrome).[91-97]

Germline mutations in the genes responsible for these autosomal dominant cancer syndromes produce different clinical phenotypes of characteristic malignancies and, in some instances, associated nonmalignant abnormalities.

The family characteristics that suggest hereditary cancer predisposition include the following:

Multiple cancers within a family.

Cancers typically occur at an earlier age than in sporadic cases (defined as cases not associated with genetic risk).

Two or more primary
cancers in a single individual. These could be multiple
primary cancers of the same type (e.g., bilateral breast cancer) or
primary cancer of different types (e.g., breast cancer and ovarian cancer in
the same individual or endometrial and colon cancer in the same individual).

Cases of male breast cancer. The inheritance risk for autosomal dominant genetic conditions is 50% for both males and females, but the differing penetrance of the genes may result in some unaffected individuals in the family.

Figure 1. BRCA1 pedigree. This pedigree shows some of the classic features of a family with a deleterious BRCA1 mutation across three generations, including affected family members with breast cancer or ovarian cancer and a young age at onset. BRCA1 families may exhibit some or all of these features. As an autosomal dominant syndrome, a deleterious BRCA1 mutation can be transmitted through maternal or paternal lineages, as depicted in the figure.

Figure 2. BRCA2 pedigree. This pedigree shows some of the classic features of a family with a deleterious BRCA2 mutation across three generations, including affected family members with breast (including male breast cancer), ovarian, pancreatic, or prostate cancers and a relatively young age at onset. BRCA2 families may exhibit some or all of these features. As an autosomal dominant syndrome, a deleterious BRCA2 mutation can be transmitted through maternal or paternal lineages, as depicted in the figure.

Figure 3. Lynch syndrome pedigree. This pedigree shows some of the classic features of a family with Lynch syndrome, including affected family members with colon cancer or endometrial cancer and a younger age at onset in some individuals. Lynch syndrome families may exhibit some or all of these features. Lynch syndrome families may also include individuals with other gastrointestinal, gynecologic, and genitourinary cancers, or other extracolonic cancers. As an autosomal dominant syndrome, Lynch syndrome can be transmitted through maternal or paternal lineages, as depicted in the figure.

There are no pathognomonic features distinguishing breast and ovarian cancers occurring in BRCA1 or BRCA2 mutation carriers from those occurring in noncarriers. Breast cancers occurring in BRCA1 mutation carriers are more likely to be ER negative, progesterone receptor negative, HER2/neu receptor-negative (i.e., triple-negative breast cancers), and have a basal phenotype. BRCA1-associated ovarian cancers are more likely to be high-grade and of serous histopathology. (Refer to the Pathology of breast cancer and Pathology of ovarian cancer sections of this summary for more information.)

Some pathologic features distinguish LS mutation carriers from noncarriers. The hallmark feature of endometrial cancers occurring in LS is mismatch repair defects, including the presence of microsatellite instability, and the absence of specific mismatch repair proteins. In addition to these molecular changes, there are also histologic changes including tumor-infiltrating lymphocytes, peritumoral lymphocytes, undifferentiated tumor histology, lower uterine segment origin, and synchronous tumors.

Considerations in Risk Assessment and in Identifying a Family History of Breast and Ovarian Cancer Risk

The accuracy and completeness of family histories must be taken into account when they are used to assess risk. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In
addition, small family sizes and premature deaths may limit the information
obtained from a family history. Breast or ovarian cancer on the
paternal side of the family usually involves more distant relatives than does breast or ovarian cancer on the
maternal side, so information may be more difficult to obtain.
When self-reported information is compared with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.[98,99] Additional limitations of relying on family histories include adoption; families with a small number of women; limited access to family history information; and incidental removal of the uterus, ovaries, and/or fallopian tubes for noncancer indications. Family histories will evolve, therefore it is important to update family histories from both parents over time. (Refer to the Accuracy of the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)

Models for Prediction of Breast Cancer Risk

Models to predict an individual’s lifetime risk of developing breast cancer are available.[100,101] In addition, models exist to predict an individual’s likelihood of having a BRCA1 or BRCA2 mutation. (Refer to the Models for prediction of the likelihood of a BRCA1 or BRCA2 mutation section of this summary for more information about these models.) Not all models can be appropriately applied to all patients. Each model is appropriate only when the patient’s characteristics and family history are similar to those of the study population on which the model was based. Different models may provide widely varying risk estimates for the same clinical scenario, and the validation of these estimates has not been performed for many models.[101,102] Table 1 summarizes the salient aspects of two of the common risk assessment models and is designed to aid in choosing the model that best applies to a particular individual.

The Claus model [103,104] and the Gail model [105] are widely used in research studies and clinical counseling. Both have limitations, and the risk estimates derived from the two models may differ for an individual patient. Several other models that include more detailed family history information are also in use and are discussed below.

For individuals with no family history of breast cancer or one FDR with breast cancer, aged ≥50 y

For individuals with no more than two FDRs or SDRs with breast cancer

For determining eligibility for chemoprevention studies

The Gail and the Claus models will significantly underestimate breast cancer risk in women from families with hereditary breast cancer susceptibility syndromes. Generally, the Claus model or the Gail model should not be the sole model used for families with one or more of the following characteristics:

Three individuals
with breast or ovarian cancer (especially when one or more breast cancers are diagnosed before age 50 years).

A woman who has both breast and ovarian cancer.

Ashkenazi Jewish ancestry with at least one case of breast or ovarian cancer (as these families are more likely to have a hereditary cancer susceptibility syndrome).

The Gail model is the basis for the Breast Cancer Risk Assessment
Tool, a computer program that is available from the National Cancer Institute by calling the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237). This version of the Gail model estimates only the risk of invasive breast cancer. The Gail model has been found to be reasonably accurate at predicting breast cancer risk in large groups of white women who undergo annual screening mammography; however, reliability varies depending on the cohort studied.[110-115] Risk can be overestimated in:

Risk could be underestimated in the lowest risk strata.[114] Earlier studies [111,112] suggested risk was overestimated in younger women and underestimated in older women. Subsequent studies
[113,114] using the modified Gail model (which is
currently used) found it performed well in all age groups. Further studies are needed to establish the validity of the Gail model in minority populations.[115] Modifications have been made to the Breast Cancer Risk Assessment Tool to incorporate data from the Women’s Contraceptive and Reproductive Experiences study. This study of more than 1,600 African American women with invasive breast cancer and more than 1,600 controls was used to develop a breast cancer risk assessment model with improved race-specific calibration.[109] Additional information for seven common low-penetrance breast cancer susceptibility alleles has not been shown to improve model performance significantly.[116,117]

A study of 491 women aged 18 to 74 years with a family history of breast cancer compared the most recent Gail model to the Claus model
in predicting breast cancer risk.[118] The two models were positively correlated (r = .55). The Gail model estimates were higher than the Claus model estimates for most participants. Presentation and discussion of the Gail model and Claus model risk estimates may be useful in the counseling setting.

The Tyrer-Cuzick model incorporates both genetic and nongenetic factors.[119] A three-generation pedigree is used to estimate the likelihood that an individual carries either a BRCA1/BRCA2 mutation or a hypothetical low-penetrance gene. In addition, the model incorporates personal risk factors such as parity, body mass index, height, and age at menarche, menopause, HRT use, and first live birth. Both genetic and nongenetic factors are combined to develop a risk estimate. Although powerful, the model at the current time is less accessible to primary care providers than the Gail and Claus models. The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm model examines family history to estimate breast cancer risk and also incorporates both BRCA1/BRCA2 and non-BRCA1/BRCA2 genetic risk factors.[120]

Other risk assessment models incorporating breast density have been developed but are not ready for clinical use.[121,122] In the future, additional models may be developed or refined to include such factors as breast density and other biomarkers.

Sellers TA, Mink PJ, Cerhan JR, et al.: The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer. Ann Intern Med 127 (11): 973-80, 1997. [PUBMED Abstract]